Synthesis of α-fluorinated phosphonoacetate derivatives using electrophilic fluorine reagents: Perchloryl fluoride versus 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor ®)

Abstract

Triethyl fluorophosphonoacetate and triethyl difluorophosphonoacetate are directly synthesized from triethyl phosphonoacetate by treatment with NaH and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor ®). Contrary to a recent report [C.J. Hamilton, S.M. Roberts, J. Chem. Soc., Perkin Trans. 1 (1999) 1051–1056], the reaction proceeded in THF without the need for DMF as a co-solvent. This method is more selective and provides greater convenience and safety than fluorination of the same substrate by treatment with t-BuOK and perchloryl fluoride (FClO 3) in toluene while offering advantages over a number of previously described methods employing alternative electrophilic fluorinating reagents or other approaches. Either the monofluoro or the difluoro product can be obtained predominantly by adjusting the molar ratio of base and Selectfluor ®. Triethyl 2-fluoro-2-phosphonopropionate (ethyl 2-(diethoxyphosphinyl)-2-fluoropropanoate) is also more conveniently made from triethyl 2-phosphonopropanoate using NaH/Selectfluor ® in THF than with FClO 3/ t-BuOK in toluene. Detailed procedures are given for obtaining the corresponding triacids in quantitative yield from the fluorinated triesters by P,P-silyldealkylation with bromotrimethylsilane followed by one-pot double hydrolysis with H 2O, and isolation as stable dicyclohexylammonium (DCHA) or pyridinium (Py) salts. Substitution of EtOH for H 2O in the latter procedure provides the CO-ester phosphonic diacids, isolated as DCHA salts, in one step. 1H, 13C, 31P and 19F NMR data are given for the compounds prepared.